Finn Moeller

In this study, the solvent-dependent divergent 1,2- and 1,3-cyclization of bicyclo[1.1.0]butanes were achieved. This protocol straightforwardly led to a diverse range of oxa-bicyclic heptanes, which may serve as lead bioisosteres in drug discovery, as well as highly functionalized cyclobutanes with exceptional diastereoselectivity. Mechanistic investigation revealed that solvent effects dominate the reaction pathway, as the rate of acid-catalyzed isomerization of BCBs varies with different solvents. Furthermore, the gram-scale reactions and various post-synthetic modifications of the products demonstrated their potential applications in synthetic chemistry.

Abstract

Bicyclo[1.1.0]butanes (BCBs) have recently garnered significant research interest as versatile precursors for synthesizing potential [n.1.1] bioisosteres and multi-functionalized cyclobutanes in a straightforward and atom-economical manner. Here, we report a solvent-dependent divergent cyclization of BCBs that provides highly diastereospecific decorated cyclobutanes and oxygen-containing bicyclo[3.1.1]heptanes (BCHeps), which serve as bioisosteres of meta-substituted arenes. Additionally, an unprecedented 1,2-difunctionalization reaction mode for BCBs was explored, thus expanding the chemical space of arene bioisosteres and highly functionalized cyclobutanes.

Nature, Published online: 11 December 2024; doi:10.1038/s41586-024-08472-z

Aromatic ring-opening metathesis

Reductive hydrolysis of inexpensive and easily accessible nitriles using Ni-tripos complex allows for the synthesis of functionalized and structurally diverse benzylic, heterocyclic, and aliphatic primary alcohols including the late-stage functionalization of bioactive molecules.

Abstract

Nitriles are an abundant class of compounds that are widely used as versatile feedstocks to produce various chemicals including pharmaceuticals, and agrochemicals as well as materials. Here we report Ni-catalyzed reductive hydrolysis of nitriles to alcohols in the presence of molecular hydrogen. This conversion likely occurs in a domino reaction sequence that first involves the hydrogenation of nitrile to primary imine, then the hydrolysis of imine, and subsequent deamination to the aldehyde, which is finally hydrogenated to the desired alcohol. Crucial for this reductive hydrolysis process is the commercially available triphos-ligated Ni-complex that enables highly efficient and selective transformation of aromatic, heterocyclic, and aliphatic nitriles including fatty nitriles to prepare functionalized primary alcohols. Further, the synthetic applicability of this Ni-based protocol is presented for the selective conversion of nitrile to alcoholic group in structurally diverse and complex drug molecules as well as agrochemicals. The resulting products, alcohols are indispensable chemicals commonly used in organic synthesis and life sciences as well as material and energy technologies.

A photocatalytic Cloke-Wilson rearrangement of crude aminocyclopropane carboxylate (ACPC) imines is reported. This leverages an energy-transfer mechanism transforming the core of ACPC to value added dehydroprolines—a useful synthetic intermediate en route to the synthesis of substituted unnatural proline derivatives. Both the 1,5-dehydroproline, as well as the uncommon 1,2-isomer are obtained from the same starting material under slightly modified conditions.

Abstract

A one-pot photocatalytic method is reported for the generation of dehydroprolines, valuable precursors to 5-aryl prolines. Imines, obtained via simple condensation of aminocyclopropane carboxylates (ACPC) with a broad range of aldehydes, were employed in this transformation without purification. We demonstrate this energy-transfer (EnT) enabled Cloke-Wilson-type rearrangement affords both the rare 1,2-dehydroprolines or the more thermodynamically favored 1,5-isomers with up to >20 : 1 selectivity in both directions, using an identical catalytic system from the same starting material. Syntheses of intermediates of bioactive molecules in high yields and selectivity highlight this enabling transformation. Mechanistic studies support the proposed triplet-triplet EnT mode of activation, distinct from the previously developed singlet excited states accessed via UV excitation.

A 3D-printable electrochemical screening reactor kit enables rapid optimization of electrosynthesis parameters through eight independent two-compartment cells. Utilizing industrially relevant electrodes, the ElectroHermes reactor provides transferable insights to scalable systems. The included open-source design files allow for customization, promoting efficient condition optimization and accelerating the electrification of the chemical industry.

Abstract

Electrosynthetic processes powered by renewable energy present a viable solution to decarbonize the chemical industry, while producing essential chemical products for modern society. However, replacing well-established thermocatalytic methods with renewable-powered electrosynthesis requires cost-efficient and highly optimized systems. Current optimization of electrolysis conditions towards industrial applications involving scalable electrodes is time-consuming, highlighting the necessity for the development of electrochemical setups aimed at rapid and material efficient testing. To address this challenge, we introduce a 3D-printed electrochemical screening reactor designed for rapid optimization of relevant electrochemical parameters, utilizing electrode and membrane materials comparable to those in scalable electrolyzers. The reactor comprises eight individual two-compartment cells that can be operated simultaneously and independently. To evaluate the reactor′s ability to provide meaningful insights on scalable cell designs, trends were compared with data from conventional scalable systems for electrochemical hydrogenations (EChH), demonstrating fast and accurate parameter optimization with the screening reactor. A detailed description of the reactor design and construction data files are provided using open-source tools, enabling easy modification for anyone. We believe this screening reactor will be a valuable tool for the scientific community, for facilitating the discovery of reactions with customized electrode designs and rapidly improving conditions in established large-scale electrolyzers.

Nature Communications, Published online: 04 December 2024; doi:10.1038/s41467-024-55043-x

Chronic pancreatitis is a risk factor for the development of pancreatic cancer. Here authors report that coxsackievirus and adenovirus receptor (CAR) expression promotes pancreatitis and pancreatic cancer upon enterovirus infections.

The enantioselective total synthesis of kalmanol was achieved by convergent and modular synthetic strategies. Two enantioenriched fragments were assembled by a Grignard reaction/ring-closing metathesis sequence. The remaining hydroxy groups were installed by precise late-stage oxidations.

Abstract

Kalmanol (1) is the first isolated kalmane-type grayanoid featuring a highly oxidized 5/8/5/5 tetracyclic carbon skeleton and 9 contiguous stereocenters. We have accomplished the efficient and asymmetric total synthesis of 1 in 16 steps from known compounds (20 steps from commercially available starting materials) by a modular synthetic strategy. A tetracyclic intermediate was prepared in a convergent manner through a Grignard reaction and a subsequent ring-closing metathesis reaction of two enantiomerically enriched fragments. The polyhydroxy groups were introduced by late-stage stereo- and regioselective oxidations.

Nature, Published online: 27 November 2024; doi:10.1038/d41586-024-03829-w

Alongside secret Santas and seasonal parties, many laboratories develop traditions to show appreciation to colleagues — from sweets and mulled wine to quizzes and ice-skating trips.

Nature Reviews Chemistry, Published online: 26 November 2024; doi:10.1038/s41570-024-00677-0

An automated electrochemical flow platform is shown to enhance reaction efficiency, minimize material use, and accelerate data generation. Through Design of Experiments, the platform optimized a reaction, achieving a six-fold improvement in yield, and holds promise for optimizing other reactions.

Studying the reductive amination of acetone with methylamine as nitrogen source using electrochemistry revealed the catalytic activity of 1 ppm Pb. In addition, the effects of the applied potential and the cathode materials on the reaction were investigated. Finally, the results were transferred to the electrochemical hydrogenation of acetone.

Abstract

The electrochemical hydrogenation (e-hydrogenation) of unsaturated compounds like imines or carbonyls presents a benign reduction method. It enables direct use of electrons as reducing agent, water as proton source, while bypassing the need for elevated temperatures or pressures. In this contribution, we discuss the active species in electrocatalytic reductive amination with the transformation of acetone and methylamine as model reaction. Surprisingly, lead impurities in the ppm-range proved to possess a significant effect in e-hydrogenation. Accordingly, the influence of applied potential and cathode material in presence of 1 ppm Pb was investigated. Finally, we transferred the insights to the reduction of acetone manifesting comparable observations as for imine reduction. The results suggest that previous studies on electrochemical reduction in the presence of lead electrodes should be re-evaluated.

Cordycicadins A−D are C₂₀ polyketides, all containing a γ-lactone fused to a 10-membered lactone. The proposed biosynthesis for the cordycicadins anticipates the formation of two more natural products which are unisolated. We report the total synthesis of (–)-cordycicadin D and the two anticipated natural products.

Abstract

Cordycicadins A−D are four C₂₀ polyketides, all containing a γ-lactone fused to a 10-membered lactone. The proposed biosynthetic pathway for the cordycicadins anticipates the formation of two more natural products which are unknown. We report the total synthesis of (–)-cordycicadin D and the two anticipated natural products 3,4-trans-cordycicadins A and B. The targets were convergently assembled, in a biomimetic fashion, via an efficient ketene trapping-intramolecular Michael addition sequence that delivered the requisite 3,4-trans-fused framework with high diastereoselectivity, enabled by the synthesis of complex dioxenones that serve as in situ ketene precursors. Recognition of the embedded polyketide symmetry enabled the use of a divergent-convergent synthetic strategy, based on the use of two products from an early-stage enzymatic resolution. The synthetic routes afforded (–)-cordycicadin D in 14 steps and 3,4-trans-cordycicadins A and B in 13 steps (longest linear sequence). This work confirms the structure of (−)-cordycicadin D and the observed instability of the anticipated natural product 3,4-trans-cordycicadin B during purification may explain why it is yet to be isolated.